The Notch protein is a transmembrane protein present in most organisms, including mammals, that has a role in regulating gene expression. Upon the binding of a ligand to the extracellular domain of Notch, the Notch protein is cleaved just outside the membrane by Tumor Necrosis Factor Alpha Converting Enzyme (TACE) releasing the extracellular domain which remains in interaction with the ligand. Then, gamma-secretase cleaves the protein just inside the membrane, releasing the intracellular domain (known as active intracellular Notch or “ICN”). The ICN translocates to the cell nucleus and activates transcription factor CSL, thus inducing gene transcription.
Faulty Notch signaling has been implicated in various disorders, including proliferative disorders. As such, inhibition of Notch signaling is an area of great interest in oncology. Gamma-secretase inhibition blocks the Notch signaling pathway and, as such, gamma-secretase inhibitors have anti-proliferative activity.
2,2-dimethyl-N-((S)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide (also referred to herein as “Compound I”) is a potent and selective inhibitor of gamma-secretase, inhibiting Notch signaling in tumor cells. It is known that xenografts treated with Compound I show reduced expression of genes associated with angiogenesis consistent with the ability of Compound Ito inhibit tumor angiogenesis. Luistro et al., Cancer Research, 69:7672-80 (2009). Interestingly, these studies showed little change in the angiogenic gene profile for the H460a xenograft.
Interleukin-6 (IL6) and interleukin-8 (IL8) are powerful cytokines that play important roles in such diverse disorders such as infection and immunity, inflammation, autoimmune disease, and cancer. Applicants have found that elevated expression of each of IL6 and IL8 confers resistance to treatment with Compound I.